DESCRIPTION (provided by principal investigator): The long-term objective of this project is to better define risk factors for age-related bone loss and fractures. This supplement to our currently funded grant entitled, "Risk Factors for Age Related Bone Loss," (R01 AR/AG 41398) expands the scope of work of the parent grant because its primary aim is to perform DXA scans in approximately 3,000 participants in the Framingham Heart Study Third Generation Cohort (Gen 3). This will nearly double the sample size available for one of the aims of the parent grant and will add over 1000 participants to another aim. In past grant cycles we had performed DXA scans on 3,804 members of two of the Framingham Cohorts (Original and Offspring Cohorts) who had genotyping completed as part of an NHLBI project called "Framingham Heart Study SNP Health Association Resource" (FHS SHARe Project) that provides 550K dense single nucleotide polymorphisms (SNPs) genome wide. The currently funded parent grant will perform a genome-wide association study (GWAS) study with our existing DXA scans. This can now be expanded to include approximately 3,000 additional Gen 3 Cohort members because the Framingham Study contract has recently been issued to examine the Gen 3 Cohort for a second time, and because the Framingham Osteoporosis Study successfully applied to the Framingham Executive Committee to perform DXA scans during this examination. This supplement will thus result in all three cohorts having BMD measured by DXA, making it the largest multi-generational osteoporosis study in the world. The DXA scans will be used for two aims. The first aim is to examine the association between lower extremity lean mass and total lean mass, measured by dual x-ray absorptiometry (DXA) and the risk for hip and non-vertebral fracture using the Framingham Fracture Registry of the Original, Offspring, and now Gen 3 Cohorts. The second aim is to perform a GWAS on a total of 6,804 participants from the Original, Offspring, and Gen 3 Cohorts of the Framingham Study with DXA measures of bone mineral density using the same FHS SHARe Project genotyping data. Replication of results will be made possible by our participation in a planned meta-analysis of GWA studies that will be conducted as part of our involvement with an international consortium of osteoporosis cohorts with GWA data called (Genetic Factors for Osteoporosis, or "GEFOS"), and a second consortium of cohort studies ("GENOMOS") in which the most significant findings from the GWA analyses will be replicated by targeted genotyping. This will ultimately lead to the identification of 4-6 of the most significant non-overlapping (r2<0.8) SNPs/candidate regions that will then be further replicated in two minority cohorts, the Tobago Bone Health Cohort (Afro-Caribbeans) and the Health ABC Cohort (African-Americans) followed by additional genotyping in the Framingham Study. This supplement greatly increases our likelihood of characterizing the role of leg muscle mass on fracture risk, and will provide substantial numbers of participants for the largest GWAS in the U.S. to use dense SNP genotyping data along with state-of-the-art skeletal imaging phenotypes to find genes related to bone density. PUBLIC HEALTH RELEVANCE: This research is relevant to public health in several ways. First it will determine how muscle mass in the legs contributes to fracture risk. Second it will identify genes that increase the risk for osteoporosis. This may eventually lead to better identification of individuals who are at increased risk for fracture in the future.